CN117843569A - 异喹啉丙烯酰胺类cdk8抑制剂及其制法和药物用途 - Google Patents
异喹啉丙烯酰胺类cdk8抑制剂及其制法和药物用途 Download PDFInfo
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Abstract
本发明属于药物化学领域,公开了式(I)所示的异喹啉丙烯酰胺类化合物或其生理上可接受的盐,所述化合物的制备方法,含有所述化合物的药物制剂,以及所述化合物在制备治疗与CDK8相关疾病药物中的临床应用。
Description
技术领域
本发明属于药物化学领域,涉及通式(I)的异喹啉丙烯酰胺类化合物或其生理上可接受的盐。这些化合物在与细胞周期蛋白依赖性激酶8(cyclin-dependent kinase 8,CDK8)相关的疾病的治疗过程中的用途,还涉及其用于治疗的方法,以及含有所述化合物的药物组合物。
背景技术
细胞周期蛋白依赖性激酶(cyclin-dependent kinases,CDKs)是丝氨酸/苏氨酸蛋白激酶家族重要成员,主要参与调控细胞周期和基因转录。CDKs单体和相应的细胞周期蛋白(Cyclins)结合形成二聚体才能被激活,目前共发现20种CDKs和30种Cyclins。CDK8主要是通过形成激酶复合物或磷酸化转录因子来调节基因转录;同时,CDK8还参与了多种肿瘤相关的信号通路,例如p53信号通路、wnt-β-catenin信号通路、TGF-β信号通路、NOTCH信号通路以及STAT1信号通路等。CDK8不仅与多种肿瘤有着明确的关联,而且还广泛参与了肿瘤发生发展过程中的能量代谢、免疫激活、侵袭和转移以及获得性耐药的产生等多个环节,是具有显著生物学特色和优势的激酶靶点。抑制CDK8具有一靶多效的特色和优势,不仅能够从肿瘤靶向治疗、免疫治疗和代谢治疗三个不同角度实现肿瘤的综合治疗,而且可有效遏制肿瘤细胞的侵袭和转移以及获得性耐药的产生,提高肿瘤靶向治疗的临床疗效。此外,CDK8也与炎症、免疫性疾病的发生发展相关。因此,靶向CDK8研发选择性小分子抑制剂有望为肿瘤、炎症及免疫性疾病等的治疗提供新手段。
随着CDK8结构生物学研究的进展,已有不同结构类型的CDK8抑制剂见诸报道。其中,SEL120、BCD-115和TSN-084进入了临床研究阶段。选择性抑制作用的实现是蛋白激酶抑制剂研发中的主要瓶颈。实现对特定激酶/激酶组的合理选择性是获得高效低毒小分子抑制剂的前提。因此,高活性高选择性结构新颖的CDK8抑制剂的发现是获得高效低毒临床药物的物质基础。
本发明旨在利用经典药物化学的药效团融合策略得到异喹啉丙烯酰胺类化合物,其具有高CDK8抑制活性及CDK8选择性,可用于治疗肿瘤、炎症及免疫性疾病等与CDK8相关的疾病。
发明内容
本发明的目的在于提供一种通式(I)所示新的异喹啉丙烯酰胺类化合物。
本发明的另一目的在于提供一种制备通式(I)所示新的异喹啉丙烯酰胺类化合物的方法。
本发明的又一目的在于提供通式(I)所示新的异喹啉丙烯酸酰胺类化合物在抑制CDK8中的用途,以及治疗与CDK8有关的疾病中的用途。
为了完成本发明的目的,本发明采用的技术方案在于提供通式(I)所示的化合物或其生理上可接受的盐:
R1选自氰基、CONR3R4;其中,R3、R4选自氢、C1-C4烷基、呋喃甲基、取代或未取代的苯基,或NR3R4共同形成取代或未取代的四元、五元或六元脂杂环;所述取代基选自甲基、甲氧基、甲胺磺酰基;
n为0,1或2;
R2选自取代或未取代的苯基、取代或未取代的苯并吲唑基、萘基、呋喃基、N-苄基-4-哌啶基;所述取代基选自卤素、C1-C6烷基、C1-C3烷氧基、苯基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基、甲磺酰基。
本发明的又一技术方案在于提供通式(IA)所示的化合物或其生理上可接受的盐:
R1选自氰基、CONR3R4;其中,R3、R4选自氢、C1-C4烷基、呋喃甲基、取代或未取代的苯基,或NR3R4共同形成取代或未取代的四元、五元或六元脂杂环;所述取代基选自甲基、甲氧基、甲胺磺酰基;
R5选自氢、卤素、C1-C6烷基、C1-C3烷氧基、苯基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基、甲磺酰基。
本发明的又一技术方案在于提供通式(IAa)所示的化合物或其生理上可接受的盐:
R5选自氢、卤素、C1-C6烷基、C1-C3烷氧基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基;
R6选自氢、甲基。
本发明的又一技术方案在于提供通式(IAb)所示的化合物或其生理上可接受的盐:
R5选自氢、卤素、C1-C6烷基、C1-C3烷氧基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基。
本发明的又一技术方案在于提供通式(IB)所示的化合物或其生理上可接受的盐:
R1选自氰基、CONR3R4;其中,R3、R4选自氢、C1-C4烷基、呋喃甲基、取代或未取代的苯基,或NR3R4共同形成取代或未取代的四元、五元或六元脂杂环;所述取代基选自甲基、甲氧基、甲胺磺酰基;
R2选自取代或未取代的苯基、取代或未取代的苯并吲唑基、萘基、呋喃基;所述取代基选自甲基、甲氧基、甲磺酰基。
本发明的又一技术方案在于提供通式(IBa)所示的化合物或其生理上可接受的盐:
R2选自取代或未取代的苯基、取代或未取代的苯并吲唑基、萘基、呋喃基;所述取代基选自甲基、甲氧基、甲磺酰基。
本发明的又一技术方案在于提供所示的化合物或其生理上可接受的盐,其特征在于,所述的化合物选自:
本发明的又一技术方案在于提供通式(I)所示的化合物制备方法,其特征在于,包括以下步骤:
式II化合物与N-溴代丁二酰亚胺反应生成式III化合物,式III化合物与丙烯酸甲酯经Heck偶联反应生成式IV化合物;式IV化合物经水解反应生成式V化合物;式V化合物与式VI化合物经缩合反应生成式I目标化合物;
其中,R1、R2和n的定义同上述限定。
为了制成药剂,可将通式(I)化合物按已知方法与合适的制药载体物质、芳香剂、调味剂和颜料用已知的方法混合,并被制成片剂或包衣的片剂,或者将其与其它的附加物质悬浮或溶解在水或油中。
本发明还涉及一种含有药物有效剂量的如通式(I)所述的化合物和药学上可接受的载体的药物组合物。
药理学研究表明,本发明的通式(I)化合物具有抑制CDK8的活性,可用于治疗与CDK8活性相关的疾病,如肿瘤、炎症、免疫性疾病等。
本发明化合物可用口服方法或非肠胃道用药。口服用药可以是片剂、胶囊剂、包衣剂,非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂,例如淀粉,明胶,阿拉伯胶,硅石,聚乙二醇,液体剂型所用的溶剂例如有水,乙醇,丙二醇,植物油类如玉米油,花生油,橄榄油等。含有本发明化合物的制剂中还可有其他助剂,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂,色素等。
有益技术效果:
实现选择性抑制是目前CDK8抑制剂研究面临的主要挑战之一。本发明化合物具有选择性抑制CDK8的特点和优势,有望提供新的安全有效的CDK8抑制剂用于治疗肿瘤、炎症及免疫性疾病等与CDK8相关的疾病。
具体实施方式
以下结合实施例对发明作进一步的说明,但这些实施例并不限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或质谱(MS)或高分辨质谱(HRMS)来确定的。NMR位移(δ)以百万分之一(ppm)的单位给出。m.p.是以℃给出的熔点,温度未加校正。柱层析一般使用200~300目硅胶为载体。NMR测定是用JEOL ECZ-400S,测定溶剂为DMSO-d6,内标为TMS,化学位移是以ppm作为单位给出。MS的测定用Agilent LC/MSD TOF液质联用仪。
实施例1:TM-1
a)100mL圆底烧瓶中分别加入6-氰基异喹啉(3.08g,20mmol),NBS(4.27g,24mmol),乙酸(100mL),90℃油浴下反应4h,反应完成后蒸出溶剂,反复用蒸馏水和甲醇洗涤得到淡黄色固体。收率:54%;1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.93(s,1H),8.60(d,J=1.2Hz,1H),8.43(d,J=8.4Hz,1H),8.14(dd,J=8.4,1.2Hz,1H).
b)100mL圆底烧瓶中依次加入上述产物(10mmol),丙烯酸甲酯(2.58g,30mmol),Pd(OAc)2(180mg,0.8mmol),K2CO3(1.4g,10mmol)和DABCO(180mg,1.6mmol),加入DMF(25mL)做溶剂,抽换气3次,N2保护下125℃油浴反应8h。反应完毕后旋蒸除部分DMF及残留的丙烯酸甲酯,用乙酸乙酯萃取,饱和食盐水洗涤三次,合并有机相,无水硫酸钠干燥后,浓缩得到浅黄色油状物,经硅胶柱层析得到白色固体TM-1。收率:87%;mp:166-167℃;1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.04(s,1H),8.93(d,J=1.2Hz,1H),8.40(d,J=16.0Hz,1H),8.40(d,J=8.4Hz,1H),8.05(dd,J=8.4,1.2Hz,1H),6.87(d,J=16.0Hz,1H),3.81(s,3H);HR-ESI-MS:m/z=239.08189[M+H]+,calcd for C14H11O2N2:239.08150.
实施例2:TM-2
a)TM-1(1.19g,5mmol)置于圆底烧瓶中,以THF(10mL):无水EtOH(10mL)的混合溶液使其完全溶解,同时加入混合溶液等体积20mL 1N NaOH水溶液,室温反应,TLC检测反应完全后,减压旋除EtOH和THF,加入蒸馏水,乙酸乙酯萃取,保留水相,加入1N HCl水溶液,调节pH至酸性,析出大量白色固体,过滤并用蒸馏水洗涤,干燥后备用。收率:85%;1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.03(s,1H),8.93(s,1H),8.39(d,J=6.8Hz,1H),8.30(d,J=12.4Hz,1H),8.05(d,J=6.8Hz,1H),6.78(d,J=12.4Hz,1H).
b)50mL圆底烧瓶中分别加入上述产物(56mg,0.25mmol),二甲胺盐酸盐(24mg,0.3mmol),HATU(228mg,0.6mmol)和DIEA(78mg,0.6mmol),DMF(5mL)为溶剂,在室温下搅8h。反应完毕后旋蒸除去部分DMF,加入乙酸乙酯,饱和食盐水洗涤三次,合并有机相干燥浓缩后经硅胶柱层析得到白色固体TM-2。收率:35%;mp:206-207℃;1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.09(s,1H),8.86(s,1H),8.38(d,J=8.4Hz,1H),8.16(d,J=15.6Hz,1H),8.04(dd,J=8.4,1.2Hz,1H),7.42(d,J=15.6Hz,1H),3.20(s,3H),2.99(s,3H);HR-ESI-MS:m/z=252.11281[M+H]+,calcd for C15H14ON3:252.11314.
实施例3:TM-3
制备方法与实施例2类似,不同之处在于,用苯胺替代实施例2中的二甲胺盐酸盐。收率:32%;mp:237-238℃;1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.50(s,1H),8.95(s,1H),8.95(s,1H),8.41(d,J=8.4Hz,1H),8.28(d,J=15.6Hz,1H),8.08(dd,J=8.4,1.2Hz,1H),7.75(d,J=7.6Hz,2H),7.38(d,J=15.6Hz,1H),7.38(d,J=1.2Hz,1H),7.11(t,J=7.6Hz,1H),7.03(d,J=15.6Hz,1H);HR-ESI-MS:m/z=300.11328[M+H]+,calcd forC19H14ON3:300.11314.
实施例4:TM-4
制备方法与实施例2类似,不同之处在于,用对甲苯胺替代实施例2中的二甲胺盐酸盐。收率:69%;mp:253-254℃;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.49(s,1H),8.94(s,1H),8.93(s,1H),8.41(d,J=8.5Hz,1H),8.26(d,J=15.7Hz,1H),8.07(dd,J=8.5,1.3Hz,1H),7.63(d,J=8.3Hz,2H),7.18(d,J=8.3Hz,2H),7.01(d,J=15.7Hz,1H),2.29(s,3H);HR-ESI-MS:m/z=314.12827[M+H]+,calcd for C20H16ON3:314.12879.
实施例5:TM-5
制备方法与实施例2类似,不同之处在于,用4-氨基-N,N-二甲基苯胺替代实施例2中的二甲胺盐酸盐。收率:32%;mp:254-255℃;1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),9.48(s,1H),8.92(s,2H),8.40(d,J=8.4Hz,1H),8.21(d,J=15.6Hz,1H),8.07(d,J=8.4Hz,1H),7.58(d,J=8.7Hz,2H),6.99(d,J=15.6Hz,1H),6.75(d,J=8.7Hz,2H),2.88(s,6H);HR-ESI-MS:m/z=343.15402[M+H]+,calcd for C21H19ON4:343.15534.
实施例6:TM-6
制备方法与实施例2类似,不同之处在于,用4-甲氧基苯胺替代实施例2中的二甲胺盐酸盐。收率:46%;mp:265-266℃;1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.49(s,1H),8.94(s,2H),8.41(d,J=8.3Hz,1H),8.25(d,J=15.8Hz,1H),8.08(d,J=8.3Hz,1H),7.67(d,J=9.1Hz,2H),6.99(d,J=15.8Hz,1H),6.95(d,J=9.1Hz,2H),3.75(s,3H);HR-ESI-MS:m/z=330.12314[M+H]+,calcd for C20H16O2N3:330.12370.
实施例7:TM-7
制备方法与实施例2类似,不同之处在于,用对三氟甲基苯胺替代实施例2中的二甲胺盐酸盐。收率:20%;mp:>300℃;1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.51(s,1H),8.97(d,J=4.0Hz,2H),8.42(d,J=8.6Hz,1H),8.34(d,J=15.7Hz,1H),8.08(dd,J=8.8,1.6Hz,1H),7.96(d,J=8.8Hz,2H),7.75(d,J=8.6Hz,2H),7.03(d,J=15.7Hz,1H);HR-ESI-MS:m/z=368.10065[M+H]+,calcd for C20H13ON3F3:368.10052.
实施例8:TM-8
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制备方法与实施例2类似,不同之处在于,用对氯苯胺替代实施例2中的二甲胺盐酸盐。收率:24%;mp:>300℃;1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.50(s,1H),8.95(d,J=1.6Hz,2H),8.41(d,J=8.4Hz,1H),8.29(d,J=15.7Hz,1H),8.08(dd,J=8.4,1.6Hz,1H),7.81-7.76(m,2H),7.45-7.42(m,2H),7.00(d,J=15.7Hz,1H);HR-ESI-MS:m/z=334.07431[M+H]+,calcd for C19H13ON3Cl:334.07417.
实施例9:TM-9
制备方法与实施例2类似,不同之处在于,用4-(4-甲基哌嗪)苯胺替代实施例2中的二甲胺盐酸盐。收率:22%;mp:>300℃;1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.49(s,1H),8.93(s,2H),8.41(d,J=8.5Hz,1H),8.23(d,J=15.7Hz,1H),8.07(dd,J=8.5,1.1Hz,1H),7.60(d,J=9.0Hz,2H),6.99(d,J=15.7Hz,1H),6.94(d,J=9.0Hz,2H),3.13-3.08(m,4H),2.47-2.44(m,4H),2.22(s,3H);HR-ESI-M S:m/z=398.19727[M+H]+,calcd forC24H24ON5:398.19754.
实施例10:TM-10
制备方法与实施例2类似,不同之处在于,用4-苯基苯胺替代实施例2中的二甲胺盐酸盐。收率:75%;mp:279-280℃;1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.50(s,1H),8.96(s,2H),8.42(d,J=8.4Hz,1H),8.31(d,J=15.7Hz,1H),8.08(dd,J=8.4,1.3Hz,1H),7.86(d,J=8.4Hz,2H),7.72-7.66(m,4H),7.48-7.45(m,2H),7.36-7.33(m,1H),7.05(d,J=15.7Hz,1H);HR-ESI-MS:m/z=376.14426[M+H]+,calcd for C25H18ON3:376.14444.
实施例11:TM-11
制备方法与实施例2类似,不同之处在于,用4-吗啉甲基苯胺替代实施例2中的二甲胺盐酸盐。收率:67%;mp:218-219℃;1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.50(s,1H),8.94(s,2H),8.41(d,J=8.4Hz,1H),8.27(d,J=15.7Hz,1H),8.08(dd,J=8.5,1.4Hz,1H),7.70(d,J=8.4Hz,2H),7.30(d,J=8.5Hz,2H),7.02(d,J=15.7Hz,1H),3.61-3.55(m,4H),3.43(s,2H),2.39-2.31(m,4H);HR-ESI-MS:m/z=399.18076[M+H]+,calcd forC24H23O2N4:399.18155.
实施例12:TM-12
制备方法与实施例2类似,不同之处在于,用4-氨基-1-苄基哌啶替代实施例2中的二甲胺盐酸盐。收率:23%;mp:213-214℃;1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.86(s,2H),8.39(d,J=8.3Hz,1H),8.22(d,J=8.0Hz,1H),8.09(d,J=16.0Hz,1H),8.05(d,J=8.4Hz,1H),7.35-7.25(m,5H),6.81(d,J=16.0Hz,1H),3.72(d,J=10.4Hz,1H),3.47(s,2H),2.79(d,J=10.4Hz,2H),2.07(t,J=10.8Hz,2H),1.82(d,J=10.8Hz,2H),1.53-1.44(m,2H);HR-ESI-MS:m/z=397.20142[M+H]+,calcd for C25H25ON4:397.20229.
实施例13:TM-13
a)100mL圆底烧瓶中分别加入6-羧基异喹啉(3.46g,20mmol),NBS(4.27g,24mmol),乙酸(100mL),90℃油浴下反应4h,反应完成后蒸出溶剂,反复用蒸馏水和甲醇洗涤得到淡黄色固体。收率:56%;1H NMR(400MHz,DMSO-d6)δ13.67(s,1H),9.45(s,1H),8.87(s,1H),8.69(d,J=1.2Hz,1H),8.35(d,J=8.4Hz,1H),8.24(dd,J=8.4,1.2Hz,1H).
b)50mL圆底烧瓶中分别加入上述产物(2.51g,10mmol),甲胺盐酸盐(810mg,12mmol),HATU(9.12g,24mmol)和DIEA(3.1g,24mmol),加入DMF(20mL)做溶剂,在室温下搅8h。反应完毕后旋蒸除去部分DMF,加入乙酸乙酯,饱和食盐水洗涤三次,合并有机相干燥浓缩后经硅胶柱层析得到白色固体。收率:57%;1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.92(q,J=4.4Hz,1H),8.84(s,1H),8.54(d,J=1.6Hz,1H),8.31(d,J=8.4Hz,1H),8.17(dd,J=8.4,1.6Hz,1H),2.87(d,J=4.4Hz,3H).
c)50mL圆底烧瓶中分别加入上述产物(1.32g,5mmol),丙烯酸甲酯(1.29g,15mmol),Pd(OAc)2(90mg,0.4mmol),K2CO3(700mg,5mmol)和DABCO(90mg,0.8mmol),加入DMF(15mL)做溶剂,抽换气3次,N2保护下125℃油浴反应8h。反应完毕后旋蒸除去部分DMF及残留的丙烯酸甲酯,加入乙酸乙酯萃取,饱和食盐水洗涤三次,合并有机相干燥浓缩后经硅胶柱层析得到TM1-13。收率:81%;mp:206-207℃;1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.98(s,1H),8.94(q,J=4.4Hz,1H),8.67(s,1H),8.44(d,J=16.0Hz,1H),8.28(d,J=8.5Hz,1H),8.14(dd,J=8.5,1.4Hz,1H),6.89(d,J=16.0Hz,1H),3.81(s,3H),2.89(d,J=4.4Hz,3H);HR-ESI-MS:m/z=271.10721[M+H]+,calcd for C15H15O3N2:271.10772.
实施例14:TM-14
a)50mL圆底烧瓶中分别加入TM-13(675mg,2.5mmol),以THF(10mL):无水EtOH(10mL)的混合溶液使其完全溶解,同时加入混合溶液等体积20mL 1N NaOH水溶液,室温反应,TLC检测反应完全后,减压旋除EtOH和THF,加入蒸馏水,乙酸乙酯萃取,保留水相,加入1N HCl水溶液,调节pH至酸性,析出大量白色固体,过滤并用蒸馏水洗涤,干燥后备用,收率:82%。
b)50mL圆底烧瓶中分别加入上述产物(64.0mg,0.25mmol),二甲胺盐酸盐(24mg,0.3mmol),HATU(114mg,0.3mmol)和DIEA(39mg,0.3mmol),加入DMF(5mL)做溶剂后,在室温下搅8h。反应完毕后旋蒸除去DMF,加入乙酸乙酯萃取,饱和食盐水洗涤三次,合并有机层干燥浓缩后经硅胶柱层析得到白色固体TM1-14。收率:32%;mp:229-230℃;1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),9.01(s,1H),8.94(q,J=4.4Hz,1H),8.66(s,1H),8.26(d,J=8.4Hz,1H),8.24(d,J=15.6Hz,1H),8.12(dd,J=8.4,1.4Hz,1H),7.42(d,J=15.6Hz,1H),3.21(s,3H),2.99(s,3H),2.87(d,J=4.4Hz,3H);HR-ESI-MS:m/z=284.13989[M+H]+,calcd for C16H18O2N3:284.13935.
实施例15:TM-15
制备方法与实施例14类似,不同之处在于,用对异丙基苯胺替代实施例14中的二甲胺盐酸盐。收率:56%;mp:251-252℃;1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.41(s,1H),8.96(q,J=4.4Hz,1H),8.86(s,1H),8.72(s,1H),8.35(d,J=15.6Hz,1H),8.29(d,J=8.5Hz,1H),8.15(dd,J=8.5,1.4Hz,1H),7.66(d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),7.02(d,J=15.6Hz,1H),2.92-2.83(d,J=4.4Hz,3H),2.88(m,1H),1.21(d,J=6.8Hz,6H);HR-ESI-MS:m/z=374.18610[M+H]+,calcd for C23H24O2N3:374.18630.
实施例16:TM-16
制备方法与实施例14类似,不同之处在于,用对氟苯胺替代实施例14中的二甲胺盐酸盐。收率:60%;mp:140-141℃;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.41(s,1H),8.96(q,J=4.4Hz,1H),8.86(s,1H),8.72(s,1H),8.36(d,J=15.6Hz,1H),8.29(d,J=8.5Hz,1H),8.15(dd,J=8.5,1.5Hz,1H),7.78(dd,J=9.1,5.0Hz,2H),7.22(t,J=9.1Hz,2H),7.00(d,J=15.6Hz,1H),2.88(d,J=4.4Hz,3H);HR-ESI-MS:m/z=350.12927[M+H]+,calcd for C20H17O2N3F:350.12993.
实施例17:TM-17
制备方法与实施例14类似,不同之处在于,用4-吗啉甲基苯胺替代实施例14中的二甲胺盐酸盐。收率:62%;mp:131-132℃;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.41(s,1H),8.96(q,J=4.4Hz,1H),8.86(s,1H),8.72(s,1H),8.35(d,J=15.6Hz,1H),8.29(d,J=8.5Hz,1H),8.15(dd,J=8.5,1.2Hz,1H),7.71(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),7.03(d,J=15.6Hz,1H),3.61-3.54(m,4H),3.43(s,2H),2.88(d,J=4.4Hz,3H),2.36-2.34(s,4H);HR-ESI-MS:m/z=431.20590[M+H]+,calcd for C25H27O3N4:431.20777.
实施例18:TM-18
制备方法与实施例14类似,不同之处在于,用4-氨基-1-苄基哌啶替代实施例14中的二甲胺盐酸盐。收率:21%;mp:152-153℃;1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.94(q,J=4.4Hz,1H),8.77(s,1H),8.65(s,1H),8.25(m,2H),8.18(d,J=15.6Hz,1H),8.12(dd,J=8.6,1.2Hz,1H),7.36-7.2(m,5H),6.81(d,J=15.6Hz,1H),3.73(d,J=8.6Hz,1H),3.48(s,2H),2.87(d,J=4.4Hz,3H),2.80(d,J=13.1Hz,2H),2.08(s,2H),1.83(d,J=13.1Hz,2H),1.53-1.44(m,2H);HR-ESI-MS:m/z=429.22641[M+H]+,calcd for C26H29O2N4:429.22850.
实施例19:TM-19
制备方法与实施例14类似,不同之处在于,用4-(4-吗啉基)苯胺替代实施例14中的二甲胺盐酸盐。收率:38%;mp:290-291℃;1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.40(s,1H),8.96(q,J=4.4Hz,1H),8.84(s,1H),8.71(s,1H),8.31(d,J=15.6Hz,1H),8.28(d,J=9.0Hz,1H),8.14(dd,J=8.8,1.4Hz,1H),7.63(d,J=9.0Hz,2H),6.99(d,J=15.6Hz,1H),6.96(d,J=8.8Hz,2H),3.77-3.72(m,4H),3.11-3.05(m,4H),2.88(d,J=4.4Hz,3H);HR-ESI-MS:m/z=417.19031[M+H]+,calcd for C24H25O3N4:417.19212.
实施例20:TM-20
制备方法与实施例14类似,不同之处在于,用对甲氧基苯胺替代实施例14中的二甲胺盐酸盐。收率:55%;mp:270-272℃;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.40(s,1H),8.97(d,J=4.8Hz,1H),8.85(s,1H),8.72(s,1H),8.38-8.26(m,2H),8.15(dd,J=8.5,1.5Hz,1H),7.73-7.65(m,2H),7.03-6.92(m,3H),3.75(s,3H),2.88(d,J=4.5Hz,3H).HR-ESI-MS:m/z=362.14992[M+H]+,calcd for C21H20O3N3:362.15088.
实施例21:TM-21
制备方法与实施例14类似,不同之处在于,用间氨基乙酰苯胺替代实施例14中的二甲胺盐酸盐。收率:45%;mp:>300℃;1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.94(s,1H),9.36(s,1H),8.90(d,J=4.8Hz,1H),8.80(s,1H),8.67(s,1H),8.29(d,J=15.6Hz,1H),8.24(d,J=8.5Hz,1H),8.10(dd,J=8.5,1.5Hz,1H),8.01(s,1H),7.49(d,J=6.5Hz,1H),7.21(d,J=6.5Hz,2H),7.00(d,J=15.6Hz,1H),2.83(d,J=4.5Hz,3H),2.01(s,3H).HR-ESI-MS:m/z=389.16028[M+H]+,calcd for C22H21O3N4:389.16082.
实施例22:TM-22
制备方法与实施例14类似,不同之处在于,用4-环己苯胺替代实施例14中的二甲胺盐酸盐。收率:43%;mp:249-251℃;1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.40(s,1H),8.96(d,J=4.8Hz,1H),8.86(s,1H),8.72(s,1H),8.34(d,J=15.6Hz,1H),8.28(d,J=8.5Hz,1H),8.15(dd,J=8.5,1.5Hz,1H),7.65(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),7.02(d,J=15.6Hz,1H),2.88(d,J=4.5Hz,3H),1.83-1.76(m,4H),1.75-1.71(m,2H),1.43-1.29(m,5H).HR-ESI-MS:m/z=414.21760[M+H]+,calcd for C26H28O2N3:414.21915.
实施例23:TM-23
制备方法与实施例14类似,不同之处在于,用4-(4-吡啶甲基)苯胺替代实施例14中的二甲胺盐酸盐。收率:50%;mp:225-227℃;1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.40(s,1H),8.95(d,J=5.1Hz,1H),8.85(s,1H),8.71(s,1H),8.52-8.43(m,2H),8.35(d,J=15.6Hz,1H),8.28(d,J=8.5Hz,1H),8.14(dd,J=8.5,1.5Hz,1H),7.69(d,J=8.5Hz,2H),7.28-7.22(m,4H),7.01(d,J=15.6Hz,1H),3.95(s,2H),2.88(d,J=4.5Hz,3H).HR-ESI-MS:m/z=423.18155[M+H]+,calcd for C26H23O2N4:423.18301.
实施例24:TM-24
制备方法与实施例14类似,不同之处在于,用4-(甲砜基)苄胺盐酸盐替代实施例14中的二甲胺盐酸盐。收率:51%;mp:293-295℃;1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.94(d,J=4.7Hz,1H),8.83(d,J=5.9Hz,1H),8.79(d,J=0.8Hz,1H),8.68(t,J=1.0Hz,1H),8.29-8.23(m,2H),8.13(dd,J=8.5,1.5Hz,1H),8.03(d,J=1.0Hz,1H),7.70(dd,J=1.6,0.9Hz,1H),7.62(dt,J=8.7,1.0Hz,1H),7.40(dd,J=8.7,1.6Hz,1H),6.89(d,J=15.7Hz,1H),4.56(d,J=5.8Hz,2H),4.04(s,3H),2.87(d,J=4.5Hz,3H).HR-ESI-MS:m/z=424.13174[M+H]+,calcd for C22H22O4N3S:424.13255.
实施例25:TM-25
制备方法与实施例14类似,不同之处在于,用2-呋喃甲胺替代实施例14中的二甲胺盐酸盐。收率:53%;mp:206-208℃;1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.93(d,J=4.8Hz,1H),8.77(d,J=6.8Hz,2H),8.66(s,1H),8.29–8.21(m,2H),8.12(dd,J=8.5,1.5Hz,1H),7.62(dd,J=1.9,0.9Hz,1H),6.85(d,J=15.6Hz,1H),6.43(dd,J=3.2,1.9Hz,1H),6.35–6.32(m,1H),4.46(d,J=5.6Hz,2H),2.87(d,J=4.5Hz,3H).HR-ESI-MS:m/z=336.13427[M+H]+,calcd for C21H20O3N3:336.13382.
实施例26:TM-26
制备方法与实施例14类似,不同之处在于,用1-(2-萘基)甲胺盐酸盐替代实施例14中的二甲胺盐酸盐。收率:55%;mp:264-266℃;1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.85-8.92(m,2H),8.77(s,1H),8.64(s,1H),8.24(d,J=7.1Hz,1H),8.21(s,1H),8.08(dd,J=8.5,1.5Hz,1H),7.84-7.88(m,3H),7.80(s,1H),7.49-7.44(m,3H),6.88(d,J=15.7Hz,1H),4.60(d,J=5.9Hz,2H),2.82(d,J=4.5Hz,3H).HR-ESI-MS:m/z=396.17010[M+H]+,calcd for C25H22O2N3:396.17065.
实施例27:TM-27
制备方法与实施例14类似,不同之处在于,用(1-甲基-1H-吲唑-5-基)甲胺替代实施例14中的二甲胺盐酸盐。收率:52%;mp:239-241℃;1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.85-8.92(m,2H),8.77(s,1H),8.64(s,1H),8.24(d,J=7.1Hz,1H),8.21(s,1H),8.08(dd,J=8.5,1.5Hz,1H),7.84-7.88(m,3H),7.80(s,1H),7.49-7.44(m,3H),6.88(d,J=15.7Hz,1H),4.60(d,J=5.9Hz,2H),2.82(d,J=4.5Hz,3H).HR-ESI-MS:m/z=400.17627[M+H]+,calcd for C23H22O2 N5:400.17680.
实施例28:TM-28
制备方法与实施例14类似,不同之处在于,用4-甲氧基苯乙胺替代实施例14中的二甲胺盐酸盐。收率:54%;mp:189-191℃;1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.89(d,J=4.7Hz,1H),8.72(s,1H),8.61(d,J=1.4Hz,1H),8.31(t,J=5.6Hz,1H),8.21(d,J=8.5Hz,1H),8.14(d,J=15.7Hz,1H),8.07(dd,J=8.5,1.5Hz,1H),7.16-7.10(m,2H),6.87-6.81(m,2H),6.76(d,J=15.7Hz,1H),3.68(s,3H),3.39(q,J=6.9Hz,2H),2.83(d,J=4.5Hz,3H),2.71(t,J=7.4Hz,2H).HR-ESI-MS:m/z=390.18051[M+H]+,calcd forC23H24O3N3:390.18122.
实施例29:TM-29
制备方法与实施例6相同,收率:24%;mp:291-292℃;1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.41(s,1H),8.85(s,1H),8.77(s,1H),8.50(s,1H),8.34(d,J=15.6Hz,1H),8.28(d,J=8.5Hz,1H),8.17(dd,J=8.5,1.4Hz,1H),7.70(s,1H),7.69-7.66(m,2H),6.99(d,J=15.6Hz,1H),6.96–6.92(m,2H),3.75(s,3H);HR-ESI-MS:m/z=348.13351[M+H]+,calcd for C20H18O3N3:348.13427.
实施例30:TM-30
制备方法与实施例7相同,收率:22%;mp:284-285℃;1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.43(s,1H),8.89(s,1H),8.80(s,1H),8.50(s,1H),8.43(d,J=15.6Hz,1H),8.29(d,J=8.6Hz,1H),8.18(d,J=8.4Hz,1H),7.97(d,J=8.4Hz,2H),7.75(d,J=8.6Hz,2H),7.72(s,1H),7.04(d,J=15.6Hz,1H);HR-ESI-MS:m/z=386.10922[M+H]+,calcd forC20H15O2N3F3:386.11109.
实施例31:TM-31
制备方法与实施例8相同,收率:25%;mp:271-272℃;1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.41(s,1H),8.86(s,1H),8.78(s,1H),8.50(s,1H),8.38(d,J=15.6Hz,1H),8.28(d,J=8.5Hz,1H),8.17(dd,J=8.5,1.4Hz,1H),7.81-7.76(m,2H),7.71(s,1H),7.46-7.41(m,2H),7.00(d,J=15.6Hz,1H);HR-ESI-MS:m/z=352.08487[M+H]+,calcd forC19H15O2N3Cl:352.08473.
实施例32:TM-32
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制备方法与实施例9相同,收率:20%;mp:299-300℃;1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.40(s,1H),8.84(s,1H),8.77(s,1H),8.50(d,J=1.4Hz,1H),8.32(d,J=15.6Hz,1H),8.27(d,J=8.6Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),7.70(s,1H),7.61(d,J=9.1Hz,2H),6.99(d,J=15.6Hz,1H),6.94(d,J=9.1Hz,2H),3.12-3.09(m,4H),2.47-2.44(m,4H),2.22(s,3H);HR-ESI-MS:m/z=416.20773[M+H]+,calcd for C24H26O2N5:416.20810.
实施例33:TM-33
a)100mL圆底烧瓶中分别加入6-羧基异喹啉(3.46g,20mmol),NBS(4.27g,24mmol),乙酸(100mL),90℃油浴下反应4h,反应完成后蒸出溶剂,反复用蒸馏水和甲醇洗涤得到淡黄色固体。收率:56%;1H NMR(400MHz,DMSO-d6)δ13.67(s,1H),9.45(s,1H),8.87(s,1H),8.69(d,J=1.2Hz,1H),8.35(d,J=8.4Hz,1H),8.24(dd,J=8.4,1.2Hz,1H).
b)50mL圆底烧瓶中分别加入上述产物(250mg,1mmol),异丙胺(71mg,1.2mmol),HATU(456mg,1.2mmol)和DIEA(387mg,3mmol),加入DMF(20mL)做溶剂,在室温下搅8h。反应完毕后旋蒸除去部分DMF,加入乙酸乙酯萃取,饱和食盐水洗涤三次,合并有机层干燥浓缩后经硅胶柱层析得到白色固体。收率:58%;1H NMR(400MHz,DMSO-d6)δ9.39(d,J=0.8Hz,1H),8.83(s,1H),8.74(d,J=7.7Hz,1H),8.53-8.50(m,1H),8.30(d,J=8.5Hz,1H),8.18(dd,J=8.5,1.6Hz,1H),4.23-4.12(m,1H),1.23(s,3H),1.22(s,3H).
c)50mL圆底烧瓶中分别加入上述产物(169mg,0.58mmol),丙烯酸甲酯(150mg,1.74mmol),Pd(OAc)2(10mg,0.046mmol),K2CO3(80mg,0.58mmol)和DABCO(11mg,0.093mmol),加入DMF(15mL)作溶剂,抽换气3次,N2保护下125℃油浴反应8h。反应完毕后旋蒸除去部分DMF及残留的丙烯酸甲酯,加入乙酸乙酯萃取,饱和食盐水洗涤三次,合并有机相干燥浓缩,经硅胶柱层析,干燥备用。收率:41%;1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.99(s,1H),8.71(d,J=7.7Hz,1H),8.63(s,1H),8.46(d,J=15.9Hz,1H),8.27(d,J=8.5Hz,1H),8.14(dd,J=8.5,1.5Hz,1H),6.90(d,J=15.9Hz,1H),4.27-4.11(m,1H),3.81(s,3H),1.25(s,3H),1.23(s,3H).
d)50mL圆底烧瓶中分别加入上述产物(72mg,0.24mmol),以THF(2mL):无水EtOH(1mL)的混合溶液使其完全溶解,同时加入混合溶液等体积3mL 1N NaOH水溶液,室温反应,TLC检测反应完全后,减压旋除EtOH和THF,加入蒸馏水,乙酸乙酯萃取,保留水相,加入1NHCl水溶液,调节pH至酸性,析出大量白色固体,过滤并用蒸馏水洗涤,干燥后备用收率:63%。1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),9.41(s,1H),8.97(s,1H),8.73(d,J=7.6Hz,1H),8.63(s,1H),8.39(d,J=15.9Hz,1H),8.27(d,J=8.5Hz,1H),8.14(dd,J=8.5,1.5Hz,1H),6.78(d,J=15.9Hz,1H),4.17(m,1H),1.25(s,3H),1.23(s,3H).
e)50mL圆底烧瓶中分别加入上述产物(42mg,0.15mmol),4-吗啉甲基苯胺(35mg,0.18mmol),HATU(68mg,0.18mmol)和DIEA(58mg,0.45mmol),加入DMF(5mL)做溶剂,在室温下搅8h。反应完毕后旋蒸除去部分DMF,加入乙酸乙酯萃取,饱和食盐水洗涤三次,合并有机层干燥浓缩后经硅胶柱层析得到。收率:49%;mp:239-241℃;1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.41(s,1H),8.86(s,1H),8.75(d,J=7.6Hz,1H),8.67(s,1H),8.41-8.34(m,1H),8.28(d,J=8.5Hz,1H),8.15(dd,J=8.5,1.5Hz,1H),7.70(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),7.03(d,J=15.5Hz,1H),4.23-4.15(m,1H),3.58(t,J=4.7Hz,4H),3.43(s,2H),2.35(s,4H),1.25(s,3H),1.23(s,3H).HR-ESI-MS:m/z=459.23764[M+H]+,calcd forC27H31O3N4:459.23907.
实施例34:TM-34
制备方法与实施例33类似,不同之处在于,第二步用环丙基甲基胺替代实施例33中的异丙胺。收率:45%;mp:244-246℃;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.41(s,1H),9.09(t,J=5.7Hz,1H),8.86(d,J=0.8Hz,1H),8.71(s,1H),8.41-8.33(m,1H),8.28(d,J=8.5Hz,1H),8.16(dd,J=8.5,1.5Hz,1H),7.70(d,J=8.5Hz,2H),7.29(d,J=8.5Hz,2H),7.02(d,J=15.6Hz,1H),3.57(t,J=4.7Hz,4H),3.42(s,2H),3.26-3.21(m,2H),2.34(s,4H),1.12-1.08(m,1H),0.50-0.45(m,2H),0.30-0.25(m,2H).HR-ESI-MS:m/z=471.23907[M+H]+,calcd for C28H31O3N4:471.23923.
实施例35:TM-35
制备方法与实施例33类似,不同之处在于,第二步用3-甲氧基-氮杂环丁烷替代实施例33中的异丙胺。收率:41%;mp:98-100℃;1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.42(s,1H),8.85(s,1H),8.43(s,1H),8.32-8.22(m,2H),7.93(dd,J=8.4,1.5Hz,1H),7.70(d,J=8.4Hz,2H),7.29(d,J=8.5Hz,2H),7.00(d,J=15.6Hz,1H),4.49(d,J=10.5Hz,1H),4.35-4.25(m,2H),4.19(d,J=9.4Hz,1H),3.93(d,J=9.4Hz,1H),3.61-3.55(m,4H),3.43(s,2H),3.23(s,3H),2.34(d,J=5.2Hz,4H).HR-ESI-MS:m/z=487.23398[M+H]+,calcdfor C28H31O4N4:487.23416.
实施例36:TM-36
制备方法与实施例33类似,不同之处在于,第二步用四氢吡咯替代实施例33中的异丙胺。收率:42%;mp:114-116℃;1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.40(s,1H),8.84(d,J=0.8Hz,1H),8.33-8.21(m,3H),7.84(dd,J=8.4,1.4Hz,1H),7.69(d,J=8.2Hz,2H),7.29(d,J=8.2Hz,2H),6.99(d,J=15.6Hz,1H),3.59-3.56(m,4H),3.54(d,J=6.8Hz,2H),3.43(s,2H),3.38(t,J=6.6Hz,2H),2.34(d,J=6.3Hz,4H),1.92(t,J=6.8Hz,2H),1.84(q,J=6.6Hz,2H);HR-ESI-MS:m/z=471.23825[M+H]+,calcd for C28H31O3N4:471.23907.
实施例37:TM-37
制备方法与实施例33类似,不同之处在于,第二步用吗啉替代实施例33中的异丙胺。收率:46%;mp:119-121℃;1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.40(s,1H),8.85(s,1H),8.29(d,J=8.4Hz,1H),8.25(m,2H),7.76(dd,J=8.4,1.4Hz,1H),7.69(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),6.99(d,J=15.6Hz,1H),3.71(s,4H),3.58(t,J=4.7Hz,8H),3.44(s,2H),2.36(s,4H).HR-ESI-MS:m/z=487.23331[M+H]+,calcd forC28H31O4N4:487.23398.
实施例38:TM-38
制备方法与实施例33类似,不同之处在于,第二步用对甲氧基苯胺替代实施例33中的异丙胺。收率:42%;mp:237-239℃;1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),10.37(s,1H),9.45(s,1H),8.90(s,1H),8.82(s,1H),8.40(d,J=15.5Hz,1H),8.34(d,J=8.7Hz,1H),8.23(dd,J=8.5,1.5Hz,1H),7.71(dd,J=8.7,6.0Hz,4H),7.29(d,J=8.5Hz,2H),7.05(d,J=15.5Hz,1H),7.00-6.95(m,2H),3.77(s,3H),3.57(t,J=4.7Hz,4H),3.43(s,2H),2.35(s,4H).HR-ESI-MS:m/z=523.23398[M+H]+,calcd for C31H31O4N4:523.23468.
实施例39:TM-39
制备方法与实施例33类似,不同之处在于,第二步用4-氨基-N-甲基苯磺酰胺替代实施例33中的异丙胺。收率:36%;mp:184-186℃;1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),10.38(s,1H),9.83(s,1H),9.45(s,1H),8.91(s,1H),8.83(s,1H),8.40(d,J=15.6Hz,1H),8.35(d,J=8.6Hz,1H),8.22(dd,J=8.6,1.5Hz,1H),7.76(t,J=2.1Hz,1H),7.70(d,J=8.5Hz,2H),7.63-7.59(m,1H),7.35(t,J=8.2Hz,1H),7.29(d,J=8.5Hz,2H),7.06(d,J=15.6Hz,1H),6.99(ddd,J=8.2,2.3,1.0Hz,1H),3.57(m,4H),3.43(s,2H),3.03(s,3H),2.34(m,4H).HR-ESI-MS:m/z=586.21187[M+H]+,calcd for C31H32O5N5S:586.21271.
实施例40:TM-40
制备方法与实施例33类似,不同之处在于,第二步用2-呋喃甲胺替代实施例33中的异丙胺。收率:40%;mp:112-114℃;1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.47(t,J=5.7Hz,1H),9.37(s,1H),8.83(d,J=0.8Hz,1H),8.73(s,1H),8.33(d,J=15.6Hz,1H),8.25(d,J=8.5Hz,1H),8.14(dd,J=8.5,1.5Hz,1H),7.69-7.64(m,2H),7.57(dd,J=1.8,0.9Hz,1H),7.25(d,J=8.5Hz,2H),6.99(d,J=15.6Hz,1H),6.38(dd,J=3.2,1.9Hz,1H),6.34-6.30(m,1H),4.53(d,J=5.5Hz,2H),3.54(t,J=4.6Hz,4H),3.39(s,2H),2.32(d,J=4.9Hz,4H).HR-ESI-MS:m/z=497.21833[M+H]+,calcd for C29H29O4N4:497.21866.
药理实验
实验例1:本发明的化合物对CDK8/cyclin C的抑制作用
方法:
采用LanthaScreen Eu激酶结合实验来评价CDK8抑制剂的活性。将CDK8/CyclinC﹑抗体混合物﹑示踪剂﹑DMSO稀释后的各浓度化合物溶液与激酶反应缓冲液(50mM HEPESpH 7.5,0.01%BRIJ-35,10mM MgCl2和1mM EGTA)混合,摇床振荡反应半分钟后于室温下孵育1小时。在酶标仪的615nm和665nm处读取并收集数据,将其转换为抑制率。化合物最大浓度值设定为10μM,该浓度下抑制率大于80%的化合物进一步测定其IC50值。以3倍梯度依次稀释得10个浓度,采用GraphPad Prism 5.0软件计算IC50值。具体的测试结果见表1-3。
表1目标化合物TM-1到TM-12的结构与分子活性
ND:活性未进行测试;
a:单浓度抑制率的数值由两次测量值取平均值得到;
b:IC50值由10个浓度(双复孔)计算得到,最大值为10μM。
表2目标化合物TM-13到TM-32的结构与分子活性
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ND:活性未进行测试;
a:单浓度抑制率的数值由两次测量值取平均值得到;
b:IC50值由10个浓度(双复孔)计算得到,最大值为10μM。
表3目标化合物TM-32到TM-40的结构与分子活性
ND:活性未进行测试;
a:单浓度抑制率的数值由两次测量值取平均值得到;
b:IC50值由10个浓度(双复孔)计算得到,最大值为10μM。
实验例2:本发明的化合物激酶选择性评价
为了考察抑制剂对CDK8的选择性,采用LanthaScreen Eu激酶结合实验,评价了部分化合物对24种激酶的选择性。选取的激酶种类包括CDKs家族的CDK1、CDK2、CDK6、CDK7和CDK9和来自于七类不同激酶家族的GSK3A、BRAF、CAMK4、CLK1、CSNK1D、DAPK1、FGFR1、JAK1、LRRK2、MARK1、MAP2K5、MAPK7、p38α、MKNK1、MST4、PDK1、PKCα、PTK2和SRC。
表4化合物对25种激酶的抑制率
*每个测试均在10μM浓度下重复两次。
CDKs(cyclin dependent kinases):细胞周期蛋白依赖性激酶;GSK3α:糖原合酶激酶3α(glycogen synthase kinase 3α);BRAF:肉瘤滤过性病毒致癌基因同源体B1(v-rafmurine sarcomaviral oncogene homolog B1);CaMK4:钙/钙调素依赖蛋白激酶4(calcium/calmodulin-dependent protein kinase 4);CLK1:CDC样激酶1(CDC likekinase 1);CSNK1D:酪氨酸激酶1D(casein kinase 1isoform delta);DAPK1:死亡相关蛋白激酶1(death-associated protein kinase 1);FGFR1:成纤维生长因子受体1(fibroblast growth factor receptor 1);JAK1:两面神激酶1(Janus kinase 1);LRRK2:亮氨酸丰富重复激酶2(leucine-rich repeat serine/threonine-protein kinase 2);MARK1:微管亲和力调节激酶1(microtubule affinity regulating kinase 1);MAP2K5:双重特异性促分裂原活化蛋白激酶激酶5(dual specificity mitogen-activated proteinkinase kinase 5);MAPK7:丝裂原激活的蛋白激酶7(mitogen-activated protein kinase7);MAPK14:丝裂原激活的蛋白激酶14(mitogen-activated protein kinase 14);MKNK1:MAP激酶相互作用丝/苏氨酸激酶1(MAP kinase-interacting serine/threonine-proteinkinase 1);MST4:丝氨酸/苏氨酸蛋白激酶4(mammalian Ste20-like kinase 4);PDK11:3-磷酸肌醇依赖性蛋白激酶1(3-phosphoinositide-dependent protein kinase);PRKCA:蛋白激酶Cα(protein kinase Cα);FAK:粘附斑激酶(focal adhesion kinase);SRC:原癌基因酪氨酸蛋白激酶(proto-oncogene tyrosine-protein kinase)。
Claims (13)
1.一种由下述通式(I)表示的异喹啉丙烯酰胺类化合物或其生理上可接受的盐,
R1选自氰基、CONR3R4;其中,R3、R4选自氢、C1-C4烷基、呋喃甲基、取代或未取代的苯基,或NR3R4共同形成取代或未取代的四元、五元或六元脂杂环;所述取代基选自甲基、甲氧基、甲胺磺酰基;
n为0,1或2;
R2选自取代或未取代的苯基、取代或未取代的苯并吲唑基、萘基、呋喃基、N-苄基-4-哌啶基;所述取代基选自卤素、C1-C6烷基、C1-C3烷氧基、苯基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基、甲磺酰基。
2.根据权利要求1所述的化合物或其生理上可接受的盐,其特征在于,所述的化合物是通式(IA)所示化合物或其生理上可接受的盐:
R1选自氰基、CONR3R4;其中,R3、R4选自氢、C1-C4烷基、呋喃甲基、取代或未取代的苯基,或NR3R4共同形成取代或未取代的四元、五元或六元脂杂环;所述取代基选自甲基、甲氧基、甲胺磺酰基;
R5选自氢、卤素、C1-C6烷基、C1-C3烷氧基、苯基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基、甲磺酰基。
3.根据权利要求2所述的化合物,其特征在于,所述的化合物是通式(IAa)所示化合物或其生理上可接受的盐:
R5选自氢、卤素、C1-C6烷基、C1-C3烷氧基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基;
R6选自氢、甲基。
4.根据权利要求2所述的化合物,其特征在于,所述的化合物是通式(IAb)所示化合物或其生理上可接受的盐:
R5选自氢、卤素、C1-C6烷基、C1-C3烷氧基、三氟甲基、N,N-二甲胺基、N-乙酰胺基、N-甲基哌嗪基、吗啉基、吗啉基甲基、吡啶基甲基。
5.根据权利要求1所述的化合物,其特征在于,所述的化合物是通式(IB)所示化合物或其生理上可接受的盐:
R1选自氰基、CONR3R4;其中,R3、R4选自氢、C1-C4烷基、呋喃甲基、取代或未取代的苯基,或NR3R4共同形成取代或未取代的四元、五元或六元脂杂环;所述取代基选自甲基、甲氧基、甲胺磺酰基;
R2选自取代或未取代的苯基、取代或未取代的苯并吲唑基、萘基、呋喃基;所述取代基选自甲基、甲氧基、甲磺酰基。
6.根据权利要求5所述的化合物,其特征在于,所述的化合物是通式(IBa)所示化合物或其生理上可接受的盐:
R2选自取代或未取代的苯基、取代或未取代的苯并吲唑基、萘基、呋喃基;所述取代基选自甲基、甲氧基、甲磺酰基。
7.具有如下结构的化合物或其生理上可接受的盐,其特征在于,所述化合物选自:
8.权利要求1~7任一项所述化合物的制备方法,其特征在于,包括以下步骤:
式II化合物与N-溴代丁二酰亚胺反应生成式III化合物,式III化合物与丙烯酸甲酯经Heck偶联反应生成式IV化合物;式IV化合物经水解反应生成式V化合物;式V化合物与式VI化合物经缩合反应生成式I目标化合物;
其中,R1、R2和n的定义同权利要求1-7。
9.一种药物组合物,其特征在于,药物组合物含有有效剂量的如权利要求1~7任一项所述的化合物或其生理上可接受的盐和在药学上可接受的载体。
10.根据权利要求9所述的药物组合物,其特征在于,所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
11.权利要求1~7任一项所述的化合物或其生理上可接受的盐在制备CDK8抑制剂中的用途。
12.权利要求1~7任一项所述的化合物或其生理上可接受的盐用于制备预防或治疗CDK8相关疾病的药物中的应用。
13.根据权利要求12所述的应用,所述的疾病选自肿瘤、炎症、和免疫性疾病。
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